RESUMO
Acute lung injury (ALI) can be induced by various injury factors, which is closely related to the inflammatory reaction and cellular ferroptosis reported recently. Glutathione peroxidase (GPX4) palys an important role in the inflammatory reaction, which also is the core regulatory protein of ferroptosis. Up-regulation of GPX4 can be helpful to inhibit the cellular ferroptosis and inflammatory reaction to treat ALI. mPEI/pGPX4 gene therapeutic system based on mannitol-modified polyethyleneimine (mPEI) was constructed. Compared with PEI/pGPX4 nanoparticles using commoditized gene vector PEI 25k, mPEI/pGPX4 nanoparticles achieved caveolae-mediated endocytosis and improved the gene therapeutic effect. mPEI/pGPX4 nanoparticles could up-regulate the gene expression of GPX4, inhibit inflammatory reaction and the cellular ferroptosis, thereby alleviating the ALIin vitroandin vivo. The finding indicated that gene therapy with pGPX4 is a potential therapeutic system for the effective treatment of ALI.
Assuntos
Lesão Pulmonar Aguda , Ferroptose , Nanopartículas , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/farmacologia , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/farmacologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapiaRESUMO
The serious side effects of cisplatin hindered its clinical application and the nanotechnology might be the potential strategy to address the limitation. However, rapid clearance in the blood circulation and ineffective controlled drug release from nanocarriers hamper the therapeutic efficacy of the nano-delivery system. We constructed a tumor microenvironment and redox dual stimuli-responsive nano-delivery system PEG-c-(BPEI-SS-Pt) by cross-linking the disulfide-containing polymeric conjugate BPEI-SS-Pt with the dialdehyde group-modified PEG2000via Schiff base. After optimized the cross-linking time, 72 h was selected to get the nano-delivery system.1H NMR and drug release assays showed that under the acidic tumor microenvironment (pH 6.5-6.8), the Schiff base can be broken and detached the PEG cross-linked outer shells, displaying the capability to release the drugs with a sequential pH- and redox-responsive manner. Moreover, PEG-c-(BPEI-SS-Pt) showed more effective anti-tumor therapeutic efficacyin vivowith no significant side effects when compared with the drug of cisplatin used in the clinic. This strategy highlights a promising platform with the dual stimuli-responsive profile to achieve better therapeutic efficacy and minor side effects for platinum-based chemotherapy.
Assuntos
Nanopartículas , Neoplasias , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Microambiente Tumoral , Bases de Schiff , Nanopartículas/química , Polímeros/química , Sistemas de Liberação de Medicamentos , Oxirredução , Neoplasias/tratamento farmacológico , Concentração de Íons de Hidrogênio , Linhagem Celular TumoralRESUMO
Pulmonary fibrosis (PF) is a chronic, progressive, and fatal lung disease with a high mortality rate. Nintedanib, as a multi-tyrosine kinase inhibitor, is widely used as the first line drug for PF patients. However, only nintedanib oral formulations are used currently in clinic and show a low drug selectivity, significant first-pass effect and low bioavailability with 4.7%, thus limiting the clinical outcome of nintedanib. In this study, nintedanib was prepared in the form of nintedanib nanocrystalline (Nib-NC) and then encapsulated with hyaluronic acid (HA) to construct a nanocrystalline-in-adhesive delivery system Nib-NC@HA with high drug loading efficacy and pulmonary bio-adhesive properties, which could avoid the first-pass effects, increase the bioavailability and reduce the systemic side effects of nintedanib. After inhalation administration of Nib-NC@HA, due to the bio-adhesive properties of HA, Nib-NC@HA could prolong the retention time of drug in the lungs and inhibit the expression of inflammation associated factors such as IL-6, IL-1ß and TNF-α in lung tissue, reduce the release of pro-fibrotic growth factor, and improve the lung function, thus showing enhanced anti-fibrotic effect than Nib-NC. The results suggested that Nib-NC@HA is an efficient and optimal targeted bio-adhesive delivery system for the lungs to treat pulmonary fibrosis.